The overall goal of this research proposal is to study the neural and molecular bases of parasite sensory behaviors. It specifically aims to understand how information about host-associated sensory cues is coded in the nervous systems of skin-penetrating human-parasitic nematodes to promote crucial steps of the parasite-host interaction. Parasitic nematodes infect over a billion people worldwide, and yet the sensory mechanisms underlying the detection and processing of specific host cues remain largely unexplored. Carbon dioxide (CO2) acts as a major host cue for multiple parasites and disease vectors. CO2 is known to elicit robust behavioral responses in a wide range of parasitic nematodes. However, the specific role of CO2 in driving parasite-host interactions is poorly understood and the neural mechanisms and molecular pathways underlying CO2-evoked responses have not been studied in any mammalian-parasitic nematode species. Using the skin-penetrating human-parasitic threadworm Strongyloides stercoralis as a model, this proposal is focused on characterizing the role of CO2 in mediating the interactions of skin-penetrating nematodes with their hosts. The major objective of this study is to elucidate the role of CO2 in mediating three crucial steps of the parasite-host interaction: (a) the process of locating hosts (host seeking), (b) development inside the host after skin penetration (activation), and (c) migration to specific tissues within the host body to complete the parasitic life cycle and establish an infection (intra-host navigation). This proposal also aims to identify and functionally characterize the neurons of the CO2-sensing microcircuit, and to identify the molecular signals that mediate the CO2-evoked responses of S. stercoralis. The outcome of this research will strengthen our understanding of how parasitic nematodes use chemosensory cues to efficiently locate their hosts and establish infections, and may enable the development of novel strategies to combat nematode infections. The findings will be the first to identify the neural circuits and molecular pathways underlying the detection of chemosensory cues in any multicellular endoparasitic organism. Further, through comparative analyses with homologous circuits and signaling pathways in the well-studied free-living nematode Caenorhabditis elegans, this study will provide novel insights into the unique adaptations of parasitic nervous systems that shape parasite- specific behaviors. !